Zenagamtide: Exploring the potential of dual GLP-1 and amylin receptor agonism

Phase 2b data showed reductions in HbA1c of up to 1.7 percentage points and body weight of almost 15% with zenagamtide in people with type 2 diabetes, supporting further investigation of this novel GLP-1 and amylin receptor agonist in phase 3 trials.

Zenagamtide (amycretin) is a novel unimolecular agonist that targets both the glucagon-like peptide-1 (GLP-1) and amylin receptors, offering a potential new approach to the treatment of type 2 diabetes and obesity. By combining these mechanisms within a single molecule, zenagamtide aims to improve glycemic control and support weight reduction, with both subcutaneous and oral formulations under investigation.

Phase 2b data presented at EASD 2026 evaluated the efficacy and safety of zenagamtide in people with type 2 diabetes, investigating multiple doses across subcutaneous and oral treatment arms. In the subcutaneous arm, HbA1c reductions of up to 1.7 percentage points from a baseline of 7.8% and weight reductions of almost 15% from a baseline body weight of approximately 99 kg were reported at 36 weeks. However, exposure to the highest doses was limited, highlighting the need for further investigation of longer-term efficacy and tolerability.

In this interview with touchENDOCRINOLOGY, Pablo Mora discusses the key findings from the phase 2b trial, the potential of combining GLP-1 and amylin receptor activity within a single molecule, and the questions that remain to be addressed in phase 3 trials, including dose tolerability and the potential effects of zenagamtide on kidney, bone, and muscle health.

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What are the key findings from the phase 2 zenagamtide trial in people with type 2 diabetes?

This was a very interesting phase 2 study in people with type 2 diabetes. Essentially, we had two studies within one trial, with participants randomized to either the subcutaneous or oral arm. The subcutaneous arm included six active treatment groups, while the oral arm included three, with all groups compared against placebo.
The study had three main objectives. First, we wanted to investigate the glycemic effects of zenagamtide, with HbA1c as the primary endpoint. Second, we looked at weight reduction at the end of the 36-week treatment period. Third, we explored other potential effects, including continuous glucose monitoring (CGM) to investigate any potential risk of hypoglycemia, as well as cardiometabolic parameters such as blood pressure, lipid profile, and high-sensitivity C-reactive protein.

What do the HbA1c and weight-loss results tell us about zenagamtide’s potential?

In the subcutaneous arm, which was the most fascinating part of the study that we presented, we saw an HbA1c reduction of 1.7 percentage points from a baseline of 7.8% at week 36. That is a very strong result. Reductions were observed across all treatment arms, with the higher doses having the greatest impact on HbA1c.
In terms of weight loss, we saw a reduction of almost 15% from baseline. The participants’ baseline body weight was close to 99 kg, so they lost up to 15% of their body weight.
One caveat of the study design is that participants were exposed to the highest doses for only a relatively short period, 4–8 weeks. Therefore, we do not yet know what the longer-term effects might be. This is why phase 3 trials need to be designed and conducted to investigate these effects further.

What do the phase 2b data tell us about the potential of combining GLP-1 and amylin activity within a single molecule?

This is a very interesting question because we already have, for example, CagriSema, which combines GLP-1 and amylin agonism in a co-formulation. With a unimolecular approach, there is the potential not only to expand treatment options, including the possibility of an oral formulation, but also to simplify production and delivery. From a manufacturing standpoint, producing and delivering a single agent is obviously simpler than using two separate agents.

What are the key questions to address as zenagamtide moves into phase 3 development?

We needed to answer a few questions, including how well the drug is tolerated as we increase the dose during titration. The protocol did not allow participants to miss a dose or step down their dose during titration. Those adjustments are typically permitted in phase 3 trials, so that is one of the things we will learn more about in the next phase of development.
We will also investigate other important outcomes, including potential effects on kidney function, bone health, and muscle health, which are all very, very fascinating areas.
Phase 3 trials are being designed in both obesity and type 2 diabetes to assess responses to lower and higher doses, with both dose levels being compared against an active comparator. We are therefore very excited about the phase 3 program and what it could tell us about zenagamtide’s potential.

Abstract details: Mora P, Aroda VR, Asong M, Blüher M, Heftdal L, Carlander ALF, Vilsen LN, Rosenstock J. Zenagamtide (amycretin), a novel unimolecular GLP-1 and amylin receptor agonist: Phase 2 results in type 2 diabetes. Oral presentation 13. Presented at: 62nd Annual Meeting of the European Association for the Study of Diabetes (EASD); September 28–October 2, 2026; Milan, Italy.